AMRI has continued to study brain anatomy by exploiting magnetic susceptibility contrast. Further experiments were performed to establish the origin of this contrast, and in parallel, applications to MS and ALS were explored. In a study of cuprizone-fed mice, which are deficient in myelin, a strong reduction in contrast between grey and white matter was found, implicating myelin as a major contributor to susceptibility contrast. Combined with our previous work, this suggest that iron, myelin, and deoxyhemoglobin explain almost all of the susceptibility contrast observed across the brain. In the major white matter fiber bundles, where iron and deoxyhemoglobin levels are low, much of the contrast may come from myelin. In addition to these measurements, computer modeling of the effect of susceptibility perturbers was performed to explain our previous result of orientation dependent contrast in the major fiber bundles. Preliminary results suggest the these orientation effects are consistent with the simulated magnetic properties of myelin. This offers opportunities for the quantification of brain myelin content. Application of susceptibility contrast to MS is ongoing. This collaborative work initially involved Francesca Bagnato of the Neuroimmunology Branch, and is currently performed with the recently established Translational Neuroradiology section of Danny Reich. The results so far have highlighted the role of iron, which is increased in microglia and macrophages in the periphery of lesions, and the reduction of myelin, which can be sensitively detected with susceptibility-weighted MRI. Future work will focus on the quantification of myelin loss with susceptibility contrast. A study of ALS, led by Mary Kay Floeter of the Spinal Physiology Unit, has demonstrated the sensitivity of susceptibility contrast at high field in detecting abnormal iron deposits in the motor cortex of ALS patients. A strong correlation was found betwwen susceptibility weighted MRI and iron histology, confirming the potential of MRI to asses abnormal brain iron deposition in-vivo. AMRI also further developed methods to study brain function based on the BOLD contrast mechanism. It has perfected methods to perform simultaneous EEG-fMRI, with the primary goal of gaining an understanding of the contributors to spontaneous brain activity. This activity is forming the basis of the growing field of brain connectivity research. Using functional MRI based on BOLD contrast, AMRI found significant areas with anti-correlated activity, both in absence and presence of and explicit visual task. Further analysis of this phenomenon revealed that it originated from blood volume effects in large veins that are downstream from the area of activation. In another experiment it was found that the vascular reactivity in the brain is altered during hypo- and hypercapnic challenges. The fact that this phenomenon can be sensitively detected with BOLD fMRI offers opportunities to study reactivity in patients with vascular disease.